Uterine leiomyomas (fibroids) are the leading indication for hysterectomy in the United States. Despite the morbidity and high medical costs associated with fibroids, there has been little epidemiologic study of this condition in the United States. Uterine leiomyomas are histologically identifiable as benign smooth muscle tumors with varying amounts of associated fibrous tissue. Many women have more than one uterine leiomyoma, but each appears to be clonally distinct. Several specific cytogenetic changes have been identified in tumor tissue, but most show no chromosomal abnormalities. These benign tumors are hormone-dependent. They develop after puberty and regress after menopause. Both estrogen and progesterone are considered important stimulants, or at least permissive factors for tumor growth. To address the research needs in this field we have designed four studies. The first, the NIEHS Uterine Fibroid Study, is a large epidemiologic study of black and white women, aged 35-49, in which the randomly selected participants were screened for fibroids with ultrasound. The second study (Fibroid Growth Study, Shyamal Peddada, PI) is a clinical study of fibroids designed to describe fibroid growth. The third study, Postpartum Uterine Regression, monitored fibroid change with pregnancy and postpartum uterine regression. The fourth study, a prospective study of fibroid incidence and growth. All these studies contributed to our research this year. We continue to analyze data from the NIEHS Uterine Fibroid Study. We found that low vitamin D status is associated with higher prevalence of fibroids in both black and white women. Dietary factors are currently being investigated. We have also analyzed data on the relationship between fibroid size and pain during sexual intercourse as well as fibroid burden and subsequent treatment needs. For the Fibroid Growth Study, stored tumor specimens from the Fibroid Growth Study were examined for genomic loss (and gain) of heterozygosity. We found that small gains were quite common, but major deletions were rare, indicating that tumors do not generally exhibit major genomic instability. Tumor tissue was also analyzed by micro-array to compare gene expression patterns by age and race categories to followup our finding about growth. For the Postpartum Uterine Regression Study, we found that the shrinkage of fibroids associated with pregnancy is attenuated for miscarriages. In addition, black women do not exhibit as much pregnancy-related tumor shrinkage as white women, and postpartum progesterone use appears to inhibit pregnancy-related tumor shrinkage. We began enrolment in a prospective study of fibroids in November, 2010. We completed enrolment of nearly 1700 African American women 23-34 during this fiscal year. The Study of Environment, Lifestyle & Fibroids (SELF) is based in Detroit, Michigan with collaboration from Henry Ford Health Systems. Participants are screened for fibroids with ultrasound at enrollment (detection limit of lesion = 0.5 cm diameter). There will be three subsequent clinic visits at approximately 20-month intervals to monitor fibroids by ultrasound examinations in order to identify onset time. Those found to have fibroids at enrollment (newly detected, not previously clinically diagnosed) as well as those who develop fibroids during the study will be followed in the same manner to assess development of additional new fibroids and to measure fibroid growth. We collected risk factor and symptom data at enrollment and then prospectively for five years. The study is designed to collect a broad spectrum of exposure data including recognized risk factors for fibroids (age of menarche, pregnancy history, alcohol use, body mass index) and potential risk factors for which there has been only suggestive data. Three primary hypotheses will be tested. (1) Vitamin D deficiency is a risk factor for fibroids, (2) Reproductive tract infections are risk factors for fibroids, and (3) A higher proportion of African ancestry is associated with increased fibroid risk (African ancestry measured by informative SNPs known to have very different frequencies between Europeans and Africans). We have completed approximately half of the ultrasound examinations for the first of the three follow-up study visits. Enrollment activities included: orientation to study, pre-enrollment self-administered questionnaire, web-based questionnaire, food-frequency questionnaire, computer-assisted telephone interview, clinic visit with ultrasound. measure of blood pressure, weight, height, skin reflectance, specimen collection (blood, urine, vaginal swabs), menstrual cycle diary to prospectively record at least one menstrual cycle and bleeding pattern, and an early life questionnaire that the participant administers to her mother (if available). We assessed intra-observer variation in fibroid measurements (for the first 96 women with fibroids) in order to help us evaluate the minimal change we will need to observe (from one ultrasound to another) to determine that tumor growth has occurred. We have also examined human papillomavirus-related (HPV) data from the first approximately 1200 participants, approximately 25% of whom had fibroids (though no prior diagnosis). Prior data from the literature showed a protective effect of abnormal Pap smear. In our sample a prior abnormal Pap smear and colposcopy (the procedure used to followup abnormal Pap results when they persist) were non-significantly associated with a reduced risk of fibroids. For women who were treated for cervical lesions (indicative of the most persistent HPV infections) there was a significant inverse association with fibroids. In an additional analysis of the first 1200 SELF participants, we found that keloids, which had been hypothesized to be associated with fibroids due to their similar extracellular matrix disarray, were not more prevalent in women women with fibroids. I also collaborate with Kathie Hartmann on the Right From the Start Study, a pregnancy study that screens participants for fibroids with ultrasound early in their pregnancies. Data from that large study showed no evidence of fibroid related decline in fecundability, but did show increased risk of C-section delivery for those with fibroids. We also replicated previous reports that early age of menarche is a risk factor for fibroids, and extended previous findings by showing that there is increased risk regardless of the type or size of fibroid seen. However, the strength of association was elevated for multiple fibroids suggesting that early age of menarche may be a marker for earlier onset disease or for increased severity.